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Trifluoromethylation process for bromo-pyridine and derivatives thereof

A technology of bromopyridine and trifluoromethyl, which is applied in the field of organic fluorine chemistry and organic chemistry, can solve the problems that the process cannot reach the yield, is suitable for large-scale production, and the reaction activity of trifluoromethylation is poor, and achieves high industrial efficiency. Application and economic value, suitable for large-scale production, and the effect of cheap bromination reagents

Active Publication Date: 2018-07-03
瑞博(杭州)医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 1. [Ph 2 SCF 3 ] + [OTf] - The reagent needs to go through 5 steps of reaction to be synthesized, and the market price is relatively high;
[0008] 2. The iodine reagent is more expensive, and after replacing the iodopyridine with a bromopyridine compound, the reagent [Ph 2 SCF 3 ] + [OTf] - The trifluoromethylation reaction activity of the trifluoromethylation is very poor, resulting in the low yield of the fluorine spectrum
[0011] Although it is mentioned in this document that the yield of trifluoromethylation of bromopyridine and its derivatives is higher when this method is adopted, the experimental data disclosed in this document are all obtained under micro-tests. The review of the preparation process shows that the process cannot achieve the yield as in the literature when the production is carried out in tons, and the trifluoromethylation reagent used in the process needs to be prepared through 6 steps of reaction, and the market price is relatively high
[0012] In summary, the prior art methods are not suitable for the preparation of bromopyridine and its derivatives on a commercial scale, so an improved and commercially viable method is needed to solve the related problems in the prior art methods and make it suitable for mass production

Method used

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  • Trifluoromethylation process for bromo-pyridine and derivatives thereof
  • Trifluoromethylation process for bromo-pyridine and derivatives thereof
  • Trifluoromethylation process for bromo-pyridine and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: the preparation of 2-bromoisonicotyl tert-butyl ester

[0046]

[0047] Add 2-bromoisonicotinic acid (48.1g, 0.238mol), NMP (120ml) into a 1L three-necked flask, start stirring, then add di-tert-butyl dicarbonate (126ml, 0.547mol), DMAP (5.82g, 0.056mol ), reacted at 25°C for 16h. 1 HNMR monitoring showed that the starting material was completely converted. NaCl (25g) and KH 2 PO 4 (25g) was dissolved in 250ml of water and added dropwise to the reaction flask, the temperature did not change significantly. After the dropwise addition was completed, 250ml of methyl tert-butyl ether was added, stirred for 15min, and extracted. Wash with 100ml of water. After concentrating under reduced pressure, a white solid was obtained with a yield of 92.6%.

Embodiment 2

[0048] Embodiment 2: the preparation of 2-trifluoromethyl isonicotinic tert-butyl ester

[0049]

[0050] in N 2 Under protection, add 2-bromoisonicotinic acid tert-butyl ester (25.7g, 0.1mol), 250ml DMF, Cu powder (19.2g, 0.3mol) into a 1L three-necked flask, start stirring, and cool to 0-5°C in an ice-water bath . Umemoto's reagent (87.6 g, 0.2 mol) was added. After stirring for 1 h in an ice-water bath, the temperature was raised to 80° C., and the reaction was carried out for 3 h. Take the reaction solution 19 FNMR analysis, with OTf as the internal standard, the yield was 93%. Dilute the reaction solution with 500ml isopropyl acetate, add dropwise 40.4g KH 2 PO 4 500ml of aqueous solution. After dripping, stir for 1h. Suction filtration, rinse filter cake with 160ml isopropyl acetate. The filtrate was allowed to stand, and the upper organic phase was separated and dried over anhydrous magnesium sulfate. Suction filtration, concentration to dryness under reduc...

Embodiment 3

[0051] Embodiment 3: Preparation of 2-trifluoromethylisonicotinic acid

[0052]

[0053] 2-Trifluoromethylisonicotinic acid tert-butyl ester (14.82g, 0.06mol) was added to 150ml of 25% hydrochloric acid by mass fraction, and reacted at 80°C for 3h. Cool to 25°C and filter with suction to obtain off-white solid. 10.54 g after drying, the yield is 92.0%.

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Abstract

The invention belongs to the field of organic chemistry and relates to a trifluoromethylation process for bromo-pyridine and derivatives thereof. The process disclosed by the invention comprises the following steps: by taking a bromo-pyridine compound with a formula a structure as a raw material, performing trifluoromethylation under the action of a Maben reagent fluoro-S-( trifluoromethyl)-dibenzothiophene salt having a formula c structure, thereby obtaining the tirfluoromethylpyridine compound with a formula b structure. The structural formula is as shown in the specification. In the formula, X- is Bronst conjugate base, R is H or -CN or halogen or C1-C6 alkyl or C1-C6 alkoxy or -OH or -R1OH or COR2 or -CO2R3 or -CONR4 or -NR5R6; R1 is C1-C6 akyl; R2, R3 and R4 are identically or differently H or C1-C6 alkyl; and the R5 and R6 are identically or differently H or O or C1-C6 alkyl or C1-C6 alkoxy.

Description

technical field [0001] The invention belongs to the field of organic chemistry, in particular to the field of organic fluorine chemistry. Background technique [0002] In recent years, scientists have discovered in research that introducing trifluoromethyl into organic compound molecules can improve the lipophilicity of the compound, thereby improving the permeability to biological membranes and tissues and the electron attraction when reacting with living organisms. To achieve the purpose of enhancing the physiological activity of compounds, with the gradual deepening of research, trifluoromethyl compounds are more and more widely used in medicine, pesticides, chemical materials, etc., so it is urgent to develop low-cost, high-yield, suitable for industrialization. Trifluoromethylation process for production. [0003] Trifluoromethylpyridine compounds are common intermediates used in the synthesis of medicines, pesticides, and chemical materials, and can be prepared from h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/26C07D213/84C07D213/85C07D213/80C07D213/803C07D213/79C07D213/82C07D213/81C07D213/61C07D213/48C07D213/50C07D213/65C07D213/68
CPCC07D213/26C07D213/48C07D213/50C07D213/61C07D213/65C07D213/68C07D213/79C07D213/80C07D213/803C07D213/81C07D213/82C07D213/84C07D213/85
Inventor 周晓聪梅本照雄李原强车大庆
Owner 瑞博(杭州)医药科技有限公司
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